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Flashcards in Disorders of globin synthesis Deck (44):

Describe normal adult hemoglobin

HbA, 2 alpha and 2 beta chains


Describe the composition of fetal hemoglobin, HbF

2 alpha and 2 gamma chains


Describe the composition of hemoglobin A2

HbA2, 2 alpha and 2 delta chains


There are two copies of the ____ gene on chromosome 16 and one __ gene as well as the gamma gene on chromosome 11

alpha on chromosome 16
beta on chromosome 11


In normal diploid cells, there are ____ alpha genes, __ beta genes, ___ delta genes, and ____ gamma genes

4 alpha, 2 beta, 2 delta, 4 gamma


The switch from Hb_ to Hb_ occurs at about six months of life

HbF--> HbA


Differentiate hemoglobinopathy from thalassemia syndromes

Hemoglobinopathy: inherited mutation of a globin gene that causes a qualitative abnormality of a globin chain. causes hemoglobin to polymerize, crystalize, or denature

Thalassemia: quantitative defect in globin syntehsis that results in imbalanced production of globin subunits, decreased production of either a or B. Excess unaffected globin can attahc to and damage the RBC membrane leading to destruction of precursors in the marrow or periphery


Thalassmeias can lead to destruction of RBCs by _________ in the marrow or _____ in the periphery

ineffective erythropoeisis


What type of hemoglobin can be missed on standard electrophoresis and why?

Barts hemoglobin (gamma4) because it is unstable and migrates rapidly. it is formed when there is decreased or absent a globin production


List the three most common genotypes that produce sickle cell disease



In sickle cell anemia, there is a ______ residue insetead of ____ in the 6th position of the beta globin gene

valine instead of glutamic acid


As HbS ______, it distorts and dehydrates the RBC causing sickling



Damage to the RBC membrane in sickle cell anemia disrupts cation homeostasis, reducing the ability of the cell to maintain a normal ____ gradient



Describe how higher levels of HbF are helpful for patients with sickle cell anemia

HbF in a cell inhibits HbS polymerization, thus decreases the likelihood of sickling. Associated with less severe disease


Describe the effects of sickle cells on NO

Hemolysis of sickled cells in the microvasculature releases heme into the plasma, which consumes NO
Hemolyzed RBCs also release arginase, which destroys arginine (a precursor for NO)


List how chronic depletion of NO leads to vasculopathy in sickle cell disease

- vasoconstriction
- increased platelet aggregation
- endothelial activation


List factors that exacerbate sickling

anything that increases the percentage of deoxyhemoglobin in the cell (causes a right shift in oxygenation curve): acidosis, increased 2,3 DPG, etc


List three major categories of complications of sickle cell disease

1. hemolytic anemia
2. vaso-occlusion (pain syndromes, acute organ damage, chronic organ damage)
3. susceptibility to infection


The hemolysis of sickle cell anemia is mainly (extravascular/ intravascular)

extravascular (some intravascular occurs)


List some complications seen in sickle cell anemia that are associated with the chronic hemolysis

risk of aplastic crisis with parvovirus infection, folate deficiency, bilirubin gallstones, iron overlaod


Sickle cell disease patients with the highest rate of _____ have the highest reticulocyte count AND the highest vaso-occulsive risk. ____ count is a marker of chronic inflammation and higher level predicts greater vaso-occulsive risk

highest rate of hemolysis
associated with hgih neutrophils


The earliest manifestation of painful crises in sickle cell disease is usually ____

dactylitis- painful swelling of hands and feet


__________ is a vaso-occlusive complication that is life threatening, usually associated with infection, and characterized by tachypnea, hypoxia, pain, cough, and infiltrates on chest X ray

acute chest syndrome


List treatment of acute chest syndrome

supplemental oxygen
transfusion or exchange


Individuals identified as having a high risk of stroke by cranial Doppler study undergo __________ therapy

chronic transfusion therapy


List some forms of chronic organ damage seen in sickle cell disease

Leg ulcers, osteonecrosis of the femoral head, pulmonary hypertension, chronic kidney disease, heart failure, retinal disease, and increased fetal loss during pregnancy


Describe why patients with sickle cell disease are at risk of infection

Micro-occlusive events eventually lead to splenic ischemia and autosplenectomy, increases susceptibility to encapsulated organisms
Infarcted tissue is vulnerable to infection- often see Slamonella and Staphylococcal infections in bone


Describe how treatment with hydroxyurea provides improvement for patients with sickle cell disease

increase HbF production, decrease inflammation, affect cell-cell interactions, and improve the hydration status of the red cell

Clinical results: children retain splenic function longer, better growth curves, fewer vaso-occlusive events, slightly higher Hb
Adults have improved QoL


The only curative treatment for sickle cell disease is ________

bone marrow transplant


List an iron chelating agent used in sickle cell disease and its purpose

deferoxamine, given intravenously, or deferasirox, given orally
may decrease the incidence of end organ failure due to iron overload.


What findings could be present in a person with sickle trait

failure to concentrate urine and possible painless hematuria- renal medulla is hypoxic, acidotic, and hyperosmolar which promotes sickling

may have sickling in severe dehydration, travel to very high altitudes


Describe hemoglobin C

Lysine replaces glutamic acid in the 6th position of the beta globin gene
Homozygocity results in mild microcytic hemolytic anemia
Many target cells on smear with rare hemoglobin crystals
Compound heterozygosity: BS/BC- cells do sickle, generally milder than S/S disease


Describe hemoglobin E

Hemoglobin mutation that cause decreased production of normal beta globin (acts like a thalassemia)
Common in SE Asian populations
Heterozygotes and homozygotes have very mild anemia, but can have compound heterozygosity with B thalassemia which can be severe


List three mechanisms of anemia in thalassemia

ineffective erythropoiesis
decreased hemoglbin synthesis


List the genotypes and clinical manifestations of a thalassemia carriers

Silent- no anemai


List the genotypes and clinical manifestations of a thalassemia trait

a-/a- or --/aa
Mild microcytic anemia, no specific treatment, avoid iron supplements


List the genotypes and clinical manifestations of HbH disease

Moderate hemolytic anemia, treat with folic acid and avoid oxidant drugs. give transfusion/ splenectomy as needed


List the genotypes and clinical manifestations of hydrops fetalis

lethal in utero


List the genotypes and clinical manifestations of B thalassemia minor

B/B0 or B/B+
Mild microcytosis with or without anemia
No treatment, avoid iron supplements


List the genotypes and clinical manifestations of B thalassemia intermedia

B+/B+ or B+/B0 or B/B0
Moderate to severe anemia
treat with folic acid, RBC transfusion or splenectomy as needed


List the genotypes and clinical manifestations of B thalassemia major

Severe, transfusion dependent anemia with iron chelation therapy. Early referral for stem cell transplant


In B thalassemia major, the only functional hemoglobins produced are ____ and _______

HbF: 2 alpha and 2 gamma
HbA2: 2 alpha and 2 delta


In the a thalassemias, there is a high percentage of _______ heomglobin in the newborn

Bart's hemoglobin- gamma4


Describe hemoglobin H

B4, found in people with three deleted a genes